Central retinal artery occlusion (CRAO), central retinal vein occlusion (CRVO), branch retinal artery occlusion (BRAO), branch retinal vein occlusion (BRVO), glaucoma, and age-related macular degeneration (AMD) are all associated with retinal ischemia. All these diseases may lead to severe sequelae and therefore the management of retinal ischemia is crucial.
Neurons, such as retinal ganglion cells (RGCs) and amacrine cells, as well as their neuronal processes, which are located in the inner retina, are vulnerable to ischemia/reperfusion (I/R). After I/R, vimentin immunoreactivity has been shown to be increased in Müller cells. Ischemia induces angiogenesis. Furthermore, in the retina angiogenesis is often disorganized and typically results in edema and hemorrhage; these have adverse effects on visual functioning. There is an urgent need for therapies that promote endogenous protective responses and prevent harmful angiogenesis. Increased levels of the hypoxia-inducible factor-1α (HIF-1α) have been found to be present after retinal ischemia. HIF-1α binds to the hypoxia response elements of hypoxia-responsive target genes, and triggers the expression of the vascular endothelium growth factor (VEGF). It has been showed that an oxidative stress in the human retinal pigment epithelium results in up-regulation of VEGF. All the above evidence suggests that overexpression of HIF-1α and VEGF in the retina or in RGCs is directly related to an ischemic insult.
Anti-VEGF antibodies are world-wide clinically used but not completely effective for treating vision-threatening retinal disorders, namely proliferative diabetic retinopathy (PDR), wet age-related macular degeneration (wAMD) and central/branch retinal vein or artery occlusion. Moreover, patients administrated with anti-VEGF agents, even though vitreous/subretinal hemorrhage and macular edema were successfully dried, poor visual results have been presented.
Xue-Fu-Zhu-Yu decoction (XFZYD) is a famous traditional Chinese medicine formula for treating cardiovascular diseases for several centuries. It has been suggested that XFZYD potentiated recombinant tissue plasminogen activator (tPA)-mediated neuroprotection against ischemic stroke in rats. It has also been indicated that XFZYD could alleviate hypoxia and protect liver sinusoidal endothelial cell function by decreased VEGF and HIF-1α.
XFZYD composition comprises eleven components, namely Radix Angelicae Sinensis (Dang Gui), Radix Rehmanniae glutinosae (Di Huang), Radix Paeoniae Rubra (Chi Shao), Rhizoma Ligustici Chuanxiong (Chuan Xiong), Semen Pruni Persicae (Táo Rén), Flos Carthami Tinctorii (Hong Hua), Radix Glycyrrhizae Uralensis (Gan Cao), Fructus Auranti (Zhi Qiao), Radix Bupleuri Chinense (Chai Hu), Radix Achyranthis Bidentatae (Niu Xi), and Radix Platycodi Grandiflori (Jie Geng). From this composition, compounds with pharmaceutical functions were identified. Ferulic acid from Dang Gui and Chuan Xiong has been proved to scavenge hydroxyl radical and provide neuroprotection against retinal ischemia. Catalpol from Di Huang has significantly enhanced the activities of antioxidative enzymes, namely superoxide dismutase, glutathione peroxidase and catalase. Peoniflorinv from Chi Shao, amygdalin from Táo Rén, hydroxysafflor yellow A (HSYA) from Hong Hua, glycyrrhizin from Gan Cao, costunolide from Zhi Qiao and saikosaponin from Chai Hu can protect against brain ischemia or injury. Furthermore, amygdalin and HSYA had synergetic effects, such as decreasing plasma viscosity and platelet aggregation. Achyranthes bidentata polysaccharides from Niu Xi have an antioxidative potential. Aqueous extract from Jie Geng such as platycodins produced significant hepatoprotective effects by decreasing nitric oxide and lipid peroxidation in dose-dependent manners.
The work described herein is to investigate the use of XFZYD composition in attenuating retinal ischemic injury. Moreover, as PKM2 and RBP2 are co-activating HIF-1α that further triggers VEGF secretion and induces possible subsequent angiogenesis in the ischemic/hypoxic conditions, whether up-regulation of VEGF and HIF-1α coexists with PKM2 and RBP2, co-activators of HIF-1α, in the ischemic retina is also included in this work.